This R21 application outlines an approach to reduce chloramines formed in human tissue after accidental exposure to chlorine gas following an industrial accident or terrorist attack. The long-term goal of this work is to develop an effective reducing agent (dechlorination treatment) suitable for intramuscular (IM) administration. We hypothesize that reducing chloramines formed in the epithelial tissue lining of the lung by hypochlorite ion after inhalation of chlorine gas is vital for minimizing or preventing permanent tissue damage. Preliminary experiments with known reductants give rapid reduction of simple amino acid chloramines in aqueous solution. However, reduction of protein chloramines in tissues exposed to hypochlorite may be more difficult using the reducing agents now available. Chlorine reacts rapidly in the respiratory tract, and modest exposure can lead to severe respiratory distress, rendering casualties impaired or unconscious. Treatment options are limited. An effective treatment for chlorine inhalation is a pressing issue for public health created by lack of available treatments and potential exposure of a large, unprepared civilian population. Chlorine is a commodity chemical manufactured and transported in tonnage quantities. A deliberate terrorist act or an accidental industrial release of chlorine in populated areas can be fatal for many and cause long-term respiratory damage in many others. Hypochlorite ion is a strong oxidizer that attacks components of epithelial cells to form a variety of oxidized species, mainly chloramines and oxidized sulfur, on proteins and polysaccharides. Some oxidation is accompanied by damaging changes to enzymes and key cellular components through free-radical reactions at chloramido groups that also damage repair mechanisms for affected proteins and cleave peptide chains. A small dose and solubility are key to the success of an IM development effort, since a paramedic responding to an incident can rapidly treat large numbers of casualties and this method is also suitable for self- administration. The advantages of the proposed approach are: (1) based on known nontoxic compounds;(2) high solubility, and (3) IM administration. The specific aims for this work are to (1) perform chemical screening of known, well-tolerated, reducing agents;(2) synthesize novel reducing agents based on the known compounds;(3) determine erythrocyte (RBC) cell wall damage using a degree of hemolysis and ektaflow cytometry;and (4) conduct in vitro efficacy studies using an epithelial cell model to evaluate the best reducing agents. PUBLIC HEALTH RELEVANCE: The release of chlorine gas as a result of an industrial accident or a terrorist attack poses a serious hazard to public health. An efficient mass treatment for an unprepared civilian population is lacking, and permanent recovery is not addressed by standard treatments. This study proposes to develop a treatment leading to improved chances of permanent recovery from chlorine inhalation.